KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations.
Eur J Hum Genet. 2012-01-18; 20(6): 645-649
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1. Eur J Hum Genet. 2012 Jun;20(6):645-9. doi: 10.1038/ejhg.2011.261. Epub 2012 Jan
KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia:
distinct phenotypes according to the nature of the mutations.
Klebe S(1), Lossos A, Azzedine H, Mundwiller E, Sheffer R, Gaussen M, Marelli C,
Nawara M, Carpentier W, Meyer V, Rastetter A, Martin E, Bouteiller D, Orlando L,
Gyapay G, El-Hachimi KH, Zimmerman B, Gamliel M, Misk A, Lerer I, Brice A, Durr
A, Stevanin G.
(1)INSERM, U975, Paris, France.
The hereditary spastic paraplegias (HSPs) are a clinically and genetically
heterogeneous group of neurodegenerative diseases characterised by progressive
spasticity in the lower limbs. The nosology of autosomal recessive forms is
complex as most mapped loci have been identified in only one or a few families
and account for only a small percentage of patients. We used next-generation
sequencing focused on the SPG30 chromosomal region on chromosome 2q37.3 in two
patients from the original linked family. In addition, wide genome scan and
candidate gene analysis were performed in a second family of Palestinian origin.
We identified a single homozygous mutation, p.R350G, that was found to
cosegregate with the disease in the SPG30 kindred and was absent in 970 control
chromosomes while affecting a strongly conserved amino acid at the end of the
motor domain of KIF1A. Homozygosity and linkage mapping followed by mutation
screening of KIF1A allowed us to identify a second mutation, p.A255V, in the
second family. Comparison of the clinical features with the nature of the
mutations of all reported KIF1A families, including those reported recently with
hereditary sensory and autonomic neuropathy, suggests phenotype-genotype
correlations that may help to understand the mechanisms involved in motor neuron
degeneration. We have shown that mutations in the KIF1A gene are responsible for
SPG30 in two autosomal recessive HSP families. In published families, the nature
of the KIF1A mutations seems to be of good predictor of the underlying phenotype
and vice versa.
PMID: 22258533 [Indexed for MEDLINE]